Concanavalin A-induced Liver Injury Research Articles

Siglec-H-/- Plasmacytoid Dendritic Cells Protect Against Acute Liver Injury by Suppressing IFN-γ/Th1 Response and Promoting IL-21+ CD4 T Cells

Siglec-H is a receptor specifically expressed in mouse plasmacytoid dendritic cells (pDCs), which functions as a negative regulator of interferon-α production and plays a critical role in pDC maturation to become antigen-presenting cells. The function of pDCs in autoimmune and inflammatory diseases has been reported. However, the effect of Siglec-H expression in pDCs in liver inflammation and diseases remains unclear. Using the model of concanavalin A-induced acute liver injury (ALI), we investigated the Siglec-H/pDCs axis during ALI in BDCA2 transgenic mice and Siglec-H-/- mice. Anti-BDCA2 antibody, anti-interleukin (IL)-21R antibody, and Stat3 inhibitor were used to specifically deplete pDCs, block IL21 receptor, and inhibit Stat3 signaling, respectively. Splenocytes and purified naive CD4 T cells and bone marrow FLT3L-derived pDCs were cocultured and stimulated with phorbol myristate acetate/ionomycin and CD3/CD28 beads, respectively. Data showed that specific depletion of pDCs aggravated concanavalin A-induced ALI. Remarkably, alanine aminotransferase, hyaluronic acid, and proinflammatory cytokines IL6 and tumor necrosis factor-α levels were lower in the blood and liver of Siglec-H knockout mice. This was associated with attenuation of both interferon-γ/Th1 response and Stat1 signaling in the liver of Siglec-H knockout mice while intrahepatic IL21 and Stat3 signaling pathways were upregulated. Blocking IL21R or Stat3 signaling in Siglec-H knockout mice restored concanavalin A-induced ALI. Finally, we observed that the Siglec-H-null pDCs exhibited immature and immunosuppressive phenotypes (CCR9LowCD40Low), resulting in reduction of CD4 T-cell activation and promotion of IL21+CD4 T cells in the liver. During T-cell-mediated ALI, Siglec-H-null pDCs enhance immune tolerance and promote IL21+CD4 T cells in the liver. Targeting Siglec-H/pDC axis may provide a novel approach to modulate liver inflammation and disease.

Glycyrrhizic acid alleviates concanavalin A-induced acute liver injury by regulating monocyte-derived macrophages

Glycyrrhizic acid alleviates concanavalin A-induced acute liver injury by regulating monocyte-derived macrophages

DNAM-1 Immunoreceptor Protects Mice from Concanavalin A-Induced Acute Liver Injury by Reducing Neutrophil Infiltration.

DNAX accessory molecule-1 (DNAM-1; CD226) is an activating immunoreceptor on T cells and NK cells. The interaction of DNAM-1 with its ligand CD155 expressed on hematopoietic and nonhematopoietic cells plays an important role in innate and adaptive immune responses. In this study, we investigated the role of the DNAM-1-CD155 axis in the pathogenesis of T cell-mediated Con A-induced acute liver injury. Unexpectedly, DNAM-1-deficient (Cd226-/-) mice exhibited more severe acute liver injury and higher concentrations of IL-6 and TNF-α than did wild-type (WT) mice after Con A injection. We found that a larger number of neutrophils infiltrated into the liver of Cd226-/- mice compared with WT mice after Con A injection. Depletion of neutrophils ameliorated liver injury and decreased IL-6 and TNF-α in Cd226-/- mice after Con A injection, suggesting that neutrophils exacerbate the liver injury in Cd226-/- mice. Hepatocytes produced more significant amounts of CXCL1, a chemoattractant for neutrophils, in Cd226-/- mice than in WT mice after Con A injection. In the coculture of hepatocytes with liver lymphocytes, either DNAM-1 deficiency in liver lymphocytes or CD155 deficiency in hepatocytes promoted CXCL1 production by hepatocytes. These results suggest that the interaction of DNAM-1 with CD155 inhibits CXCL1 production by hepatocytes, leading to ameliorating acute liver injury.

Toll-like receptor-7 signaling in Kupffer cells exacerbates concanavalin A-induced liver injury in mice.

Concanavalin A (ConA) is a plant lectin that can induce immune-mediated liver damage. ConA induced liver damage animal model is a widely accepted model that can mimic clinical acute hepatitis and immune-mediated liver injury in humans. Toll-like receptor-7 (TLR7), a member of the TLR family, plays a key role in pathogen recognition and innate immune activation. The aim of this study was to examine the role of TLR7 in the pathogenesis of ConA-induced liver injury. Acute liver injury was induced by intravenous injection with ConA in WT (wild-type) and TLR7 knockout (KO) mice. Results showed that attenuated liver injury in TLR7-deficient mice, as indicated by increased survival rate, decreased aminotransferase levels, and reduced pathological lesions, was associated with decreased release of pro-inflammatory cytokines in livers. Consistently, significantly decreased proliferation of CD4+ T cell was detected in ConA-stimulated TLR7-deficient splenocytes, but not in CD3/CD28 stimulated TLR7-deficient CD4+ T cells. Moreover, TLR7 deficiency in KCs specifically suppressed the expression of TNF-α (tumor necrosis factor-α). Depletion of KCs abolished the detrimental role of TLR7 in ConA-induced liver injury. Taken together, these results demonstrate that TLR7 can regulate the expression of TNF-α in KCs, which is necessary for the full progression of ConA-induced liver injury.

Administration of spermidine attenuates concanavalin A-induced liver injury.

A previous study revealed that treatment with the anticoagulant heparin attenuated concanavalin A (ConA)-induced liver injury. The administration of spermidine (SPD) increased urokinase-type plasminogen activator (uPA) levels in the serum. uPA is clinically used for the treatment of some thrombotic diseases such as cerebral infarction. Therefore, SPD may attenuate ConA-induced liver injury that is exacerbated by blood coagulation. The present study investigated the effect of SPD on liver injury in mice with autoimmune hepatopathy induced by ConA. A model of liver injury was created by intravenous injection of ConA into mice. SPD was administered in free drinking water and was biochemically and pathologically examined over time. The administration of SPD to ConA-treated mice significantly reduced liver injury. However, SPD treatment upregulated the mRNA expression of TNF-α and IFN-ϒ in the livers of ConA-treated mice. In contrast, the mRNA expression of tissue factor in the livers of SPD-treated mice was decreased after ConA injection. The frequency of lymphocytes and lymphocyte activation were not affected by SPD administration in ConA-treated mice. SPD treatment increased uPA levels in the serum and decreased the level of D-dimer in ConA-treated mice. Moreover, SPD decreased fibrin in the livers of ConA-treated mice. These results indicated that SPD treatment increased anticoagulant ability by increasing of uPA and attenuated ConA-induced liver injury.

Meteorin-like protein overexpression ameliorates fulminant hepatitis in mice by inhibiting chemokine-dependent immune cell infiltration.

Myokines, which are recently identified cytokines secreted by skeletal muscle in response to stimulation, are crucial for the maintenance of liver function. Fulminant hepatitis (FH) is a life-threatening pathological condition with severe hepatic dysfunction. In this study, we investigated the role of meteorin-like (METRNL), a new myokine, in the pathogenesis of FH. We compared serum samples and liver tissues from FH patients and healthy controls and found that hepatic and serum METRNL levels were significantly increased in FH patients, and serum METRNL levels were related to disease severity in FH patients. We then established a concanavalin A-induced FH model in METRNL-overexpressing and control mice. We found that hepatic METRNL levels in FH mice were significantly increased, and METRNL in the liver was mainly derived from macrophages. In the cultured mouse macrophage line (RAW264.7 cells) and mouse primary peritoneal macrophages (PMs), METRNL overexpression significantly inhibited the release of the proinflammatory cytokines TNF and IL-1β. In METRNL-overexpressing mice, concanavalin A-induced liver injury was significantly ameliorated. Moreover, METRNL overexpression significantly reduced chemokine-dependent inflammatory cell infiltration into the liver. METRNL overexpression also suppressed liver CD4+ T cell differentiation into Th 1 cells and inhibited the secretion of Th 1 cytokines. Taken together, these data suggest that METRNL overexpression effectively ameliorates FH. Therefore, METRNL may serve as a potential biomarker and therapeutic target for FH.

MicroRNA-124 expression in Kupffer cells modulates liver injury by targeting IL-6/STAT3 signaling

MicroRNA-124 (miR-124) is related to liver injury due to chronic hepatitis B (CHB) and hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). However, the mechanism whereby miR-124 regulates liver inflammation remains unknown. In this study, we show that serum miR-124 serves as a compensatory predictive factor for organ failure and the 28-day prognosis of patients with HBV-ACLF. Moreover, within a mouse model of concanavalin A-induced acute liver injury, miR-124 is highly expressed in Kupffer cells. Overexpression of miR-124 significantly decreases interleukin-6 (IL-6) secretion, and relieves pathological liver necrosis to a great extent. Mechanistically, miR-124 directly targets the 3′-untranslated region of signal transducer and activator of transcription 3 (STAT3) and inhibits IL-6/STAT3 signaling, which reduces pro-inflammatory Kupffer cell polarization. Collectively, our findings suggest that miR-124 can potentially serve as a predictive biomarker for HBV-ACLF prognosis and may represent a promising therapeutic target for relieving severe liver injury resulting from cytokine storms.

Liver infiltration of multiple immune cells during the process of acute liver injury and repair.

Immune cells, including neutrophils, natural killer (NK) cells, T cells, NKT cells and macrophages, participate in the progression of acute liver injury and hepatic recovery. To date, there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery. To investigate the infiltration changes of various immune cells in acute liver injury models over time, and to study the relationship between the changes in leukocyte cell-derived chemotaxin 2 (LECT2) and the infiltration of several immune cells. Carbon tetrachloride- and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively. The quantitative changes in various immune cells were monitored at different time points. Serum samples were collected, and liver tissues were harvested. Ly6G, CD161, CD4, CD8 and F4/80 staining were used to indicate neutrophils, NK/NKT cells, CD4+ T cells, CD8+ T cells and macrophages, respectively. Lect2-KO mice were used to detect the function of LECT2. During the injury and repair process, different types of immune cells began to increase, reached their peaks and fell into decline at different time points. Furthermore, when the serum alanine transaminase (ALT) and aspartate transaminase (AST) indices reverted to normal levels 7 d after the injury, the infiltration of immune cells still existed even 14 d after the injury, showing an obvious lag effect. We found that the expression of LECT2 was upregulated in acute liver injury mouse models, and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice. Compared with wild-type mice, Lect2-KO mice had different immune cell infiltration. The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair. LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.

S-Propargyl-cysteine prevents concanavalin A-induced immunological liver injury in mice

Context S-Propargyl-cysteine (SPRC), an endogenous H2S modulator, exerts anti-inflammatory effects on cardiovascular and neurodegenerative disease, but it remains unknown whether SPRC can prevent autoimmune hepatitis. Objective To evaluate the preventive effect of SPRC on concanavalin A (Con A)-induced liver injury and uncover the underlying mechanisms. Materials and methods Mice were randomly divided into five groups: control, Con A, SPRC (5 and 10 mg/kg injected intravenously once a day for 7 days), and propargylglycine (PAG; 50 mg/kg injected intraperitoneally 0.5 h before SPRC for 7 days). All mice except the controls were intravenously injected with Con A (20 mg/kg) on day 7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using kits. Inflammatory cytokines (TNF-α and IFN-γ) in the blood and in the liver were detected by ELISA Kit and real-time PCR, respectively. The expression of mitogen-activated protein kinase (MAPK) pathway proteins (p-JNK and p-Akt) and apoptosis proteins (Bax and Bcl-2) was detected using western blotting. Results SPRC reduced the levels of AST (p < 0.05) and ALT (p < 0.01) and decreased the release of the inflammatory cytokines. Mechanistically, SPRC increased H2S level (p < 0.05) and promoted cystathionine γ-lyase (CSE) expression (p < 0.05). SPRC inhibited the MAPK pathway activation and the apoptosis pathway. All the effects of SPRC were blocked by the CSE inhibitor PAG. Conclusions SPRC prevents Con A-induced liver injury in mice by promoting CSE expression and producing endogenous H2S. The mechanisms include reducing the release of inflammatory cytokines, attenuating MAPK pathway activation, and alleviating apoptosis.

Lamina propria interleukin 17 A aggravates natural killer T-cell activation in autoimmune hepatitis.

Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)-17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL-17A in a mice model of immune-mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A-induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then, the natural killer (NK) T cells were overactivated by the accumulated IL-17A in the liver in the Con A and S. typhimurium administration group. IL-17A could activate NKT cells by inducing CD178 expression via IL-4/STAT6signaling. Furthermore, via the portal tract, the laminae propria mucosal-associated invariant T (MAIT)-cell-derived IL-17A could be the original driver of NKT cell overactivation in intragastric administration of S. typhimurium and Con A injection. In IL-17A-deficient mice, Con A-induced liver injury and NKT cell activation were alleviated. However, when AAV-sh-mIL-17a was used to specifically knock down IL-17A in liver, it seemed that hepatic IL-17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A-induction, laminae propria MAIT-derived IL-17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.

Magnesium Isoglycyrrhizinate Ameliorates Concanavalin A-Induced Liver Injury by Inhibiting Autophagy.

Background and Aims: Acute liver failure (ALF) is a type of liver injury that is caused by multiple factors and leads to severe liver dysfunction; however, current treatments for ALF are insufficient. Magnesium isoglycyrrhizinate (MgIG), a novel glycyrrhizin extracted from the traditional Chinese medicine licorice, has a significant protective effect against concanavalin A (ConA)-induced liver injury, but its underlying therapeutic mechanism is unclear. Hence, this study aims to explore the potential therapeutic mechanism of MgIG against ConA-induced immune liver injury. Methods: ConA (20 mg/kg, i. v.) was administered for 12 h to construct an immune liver injury model, and the treatment group was given MgIG (30 mg/kg, i. p.) injection 1 h in advance. Lethality, liver injury, cytokine levels, and hepatocyte death were evaluated. The level of autophagy was evaluated by electron microscopy, RT-PCR and western blotting, and hepatocyte death was assessed in vitro by flow cytometry. Results: MgIG significantly increased the survival rate of mice and ameliorated severe liver injury mediated by ConA. The decrease in the number of autophagosomes, downregulation of LC3b expression and upregulation of p62 expression indicated that MgIG significantly inhibited ConA-induced autophagy in the liver. Reactivation of autophagy by rapamycin (RAPA) reversed the protective effect of MgIG against ConA-induced liver injury. Compared with MgIG treatment, activation of autophagy by RAPA also promoted the expression of liver inflammation markers (IL-1β, IL-6, TNF-α, CXCL-1, CXCL-2, CXCL-10, etc.) and hepatocyte death. In vitro experiments also showed that MgIG reduced ConA-induced hepatocyte death but did not decrease hepatocyte apoptosis by inhibiting autophagy. Conclusion: MgIG significantly ameliorated ConA-induced immune liver injury in mice by inhibiting autophagy. This study provides theoretical support for the ability of MgIG to protect against liver injury in clinical practice.

Thymoquinone Attenuates Immune Mediated Liver Injury Induced by Concanavalin A in Mice

Autoimmune hepatitis is an inflammatory disease and its incidence has been increasing. The features of hepatitis are the release of inflammatory cytokines, the elevation of AST and ALT, and hepatocyte apoptosis and necrosis. Concanavalin A considered as essential model represents the acute immune-mediated liver damage in rodents. Thymoquinone is well known herbal compound that exert hepatoprotective, anti-inflammatory, and antioxidant activity. In this study, we focus on the immunoregulatory and liver protective effect of thymoquinone in a mouse model of concanavalin A-induced liver injury.&#x0D; Twenty-four male mice were randomly divided into four groups each containing six animals: Negative control group, concanavalin A model group, thymoquinone 15mg/kg group, and thymoquinone 30mg/kg group. Blood was collected to detect the activities of alanine transaminase (ALT) and aspartate transaminase (AST) as well as liver tissue for the detection of tumor necrosis factor &#x0D; levels, after 8 hours of concanavalin A injection.&#x0D; Injecting mice with concanavalin resulted in a dramatic increase in serum level of both ALT and AST which indicate severe liver tissue damage with a significant increase in inflammatory cytokines TNF alpha -&#x0D; and INF levels, with a notable increase in NF-kB gene expression in mice liver tissue homogenate. Thymoquinone pretreatment revealed a dose-dependent increase in liver tissue protection.&#x0D; Conclusion: Thymoquinone has hepatoprotective and immune modulatory effects in concanavalin A induced immune mediated liver damage. Thymoquinone exerted its effect through attenuating NF and its downstream effectors TNF and INF in a dose dependent manner.

The Potential Protective Effect of Iridoid Glycosides Isolated From Osmanthus fragrans Seeds Against the Development of Immune Liver Injury in Mice.

Objective: The iridoid glycosides were extracted and separated from Osmanthus fragrans seeds, and the potential protective effect of Osmanthus fragrans seed extract on concanavalin A-induced immune liver injury in mice was studied. Methods: Osmanthus fragrans seeds were extracted by 95% ethanol reflux. Then, the iridoid glycosides were enriched by extraction refined through petroleum ether (60°C–90°C), ethyl acetate, and water-saturated n-butanol in sequence, so as to purify the n-butanol part (Osmanthus fragrans seed’s n-butanol extraction, OFSN) by macroporous resin. Specnuezhenide and Nuezhenoside G13 were used as the reference substances to determine the concentration of iridoid glycosides by HPLC. On this basis, a mouse immune liver injury model was established by tail intravenous concanavalin A (20 mg/kg); the contents of serum ALT, AST, IFN-γ, and TNF-α and the contents of liver tissue MDA and SOD were determined; the pathological changes of the liver by HE staining were observed; and the expression levels of p38MAPK and p-p38mapk in liver tissue were detected by WB. Results: The linearity, precision, repeatability, recovery, and stability of HPLC all met the requirements by validating with the methodology. The contents of Specnuezhenide and Nuezhenoside G13 in the n-butanol extracts were 39.20% and 39.88%, respectively. Actually, their contents can reach up to 82.56% and 87.9% after being purified by macroporous resin. The results of animal experiments show that OFSN could significantly reduce the liver and spleen index, reduce the ALT and AST contents in plasma and the MDA content in liver tissue, and then increase the SOD content. Besides, OFSN could also reduce the plasma IFN-γ and TNF-α levels. The HE staining result indicates that the pathological changes in the liver tissues of mice treated with OFSN are alleviated to different degrees while the WB result suggests that OFSN could significantly inhibit the expression of p-p38mapk. Conclusion: Osmanthus fragrans seeds are rich in iridoid glycosides, which has a good protective effect on mouse immune liver injury caused by concanavalin A. The mechanism may be related to inhibiting the phosphorylation of p38MAPK, inhibiting the release of inflammatory mediators, improving the antioxidant capacity of liver cells, and weakening the occurrence of lipid peroxidation.

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury.

BackgroundSphingolipids produce pleiotropic signaling pathways, and participate in the pathological mechanism of hepatocyte apoptosis and necrosis during liver injury. However, the role of glucosylceramide synthase (GCS)–key enzyme that catalyzes the first glycosylation step, in liver injury is still vague.MethodsAll experiments were conducted using 7–9-week-old pathogen-free male C57BL/6 mice. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected in murine models of liver disease, in addition to histological characterization of liver injuries. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression of the GCS, matrix metallopeptidase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes. The GCS was observed through a fluorescence microscope, and the flow cytometry was used to detect hepatocyte apoptosis. The concentrations of serum IL-4, IL-6, and IL-10 were measured using enzyme-linked immune-sorbent assay (ELISA) kit. MMP-1 and TIMP-1 protein expression was measured via western blot (WB) analysis.ResultsCon A is often used as a mitogen to activate T lymphocytes and promote mitosis. A single dose of Con A injected intravenously will cause a rapid increase of ALT and AST, which is accompanied by the release of cytokines that cause injury and necrosis of hepatocytes. In this study, we successfully induced acute immune hepatitis in mice by Con A. Con A administration resulted in GCS upregulation in liver tissues. Moreover, the mice in the Con A group had significantly higher levels of ALT, AST, IL-4, IL-6, IL-10 and increased hepatocyte apoptosis than the control group. In contrast, all of the aforementioned genes were significantly downregulated after the administration of a GCS siRNA or Genz-123346 (i.e., a glucosylceramide synthase inhibitor) to inhibit the GCS gene. Additionally, the histopathological changes observed herein were consistent with our ALT, AST, IL-4, IL-6, and IL-10 expression results. However, unlike this, hepatocyte apoptosis has been further increased on the basis of the Con A group. Moreover, our qRT-PCR and WB results indicated that the expression of MMP-1 in the Con A group was significantly lower than that in the control group, whereas TIMP-1 exhibited the opposite trend. Conversely, MMP-1 expression in the GCS siRNA and Genz-123346 groups was higher than that in the Con A group, whereas TIMP-1 expression was lower.ConclusionsGCS inhibition reduces Con A-induced immune-mediated liver injury in mice, which may be due to the involvement of GCS in the hepatocyte repair process after injury.

Daidzein ameliorated concanavalin A-induced liver injury through the Akt/GSK-3β/Nrf2 pathway in mice.

BackgroundDaidzein is a soybean isoflavone that has been shown in previous studies to have anti-inflammatory and antioxidant effects. However, it remains unknown whether daidzein plays a protective role against concanavalin A (Con A)-induced autoimmune hepatitis (AIH).MethodsIn this study, an animal model of AIH was constructed by intravenous injection of Con A (15 mg/kg). Daidzein (200 mg/kg/d) was intraperitoneally administered to mice for 3 days before the Con A injection. Alpha mouse liver 12 (AML-12) cells were incubated in the absence or presence of daidzein to determine whether daidzein can alleviate Con A-induced hepatotoxicity.ResultsThe findings showed that pretreatment with daidzein significantly reduced Con A-induced oxidative stress and hepatocyte apoptosis in Con A-induced liver injury. Pretreatment with daidzein significantly prevented the decrease of intrahepatic protein levels of phosphorylated Akt (p-Akt), phosphorylated GSK3β (p-GSK3β), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NOQ1 (NAD(P)H quinone dehydrogenase 1) in response to Con A administration. Meanwhile, malondialdehyde (MDA) production was reduced, and glutathione peroxidase (GPX), superoxide dismutase (SOD) activity, and SOD2 mRNA expression were elevated in daidzein-pretreated livers. In in vitro experiments, daidzein pretreatment prevented Con A-induced murine hepatocyte death. This effect was partly diminished by an inhibitor of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.ConclusionsThese results indicate that daidzein pretreatment attenuates Con A-induced liver injury through the Akt/GSK3β/Nrf2 pathway. Our findings provide new insights into the use of plant-derived products for AIH treatment beyond immunosuppression.

Diallyl trisulfide protects against concanavalin A-induced acute liver injury in mice by inhibiting inflammation, oxidative stress and apoptosis

AimsTo investigate the protective effects and underlying mechanisms of diallyl trisulfide (DATS) against acute liver injury induced by concanavalin A (Con A). Materials and methodsDATS (20, 40, 80 mg/kg) were gavaged to ICR mice 1 h before Con A (20 mg/kg) tail vein injection. The survival rate of mice, alterations of serum biochemical markers and liver histopathology were measured to evaluate the protective effects of DATS at 24 h after Con A exposure. The indexes of inflammation, oxidative stress and apoptosis were determined to explore the possible mechanisms. Key findingsDATS pretreatment increased survival rate of mice in a dose-dependent manner, inhibited the increase of liver-to-spleen ratio and serum liver injury markers, and attenuated liver pathological damage induced by Con A. Further study showed that DATS pretreatment inhibited the activation of Kupffer cells/macrophages, release of tumor necrosis factor-α (TNF-α) and Caspase-1-dependent inflammation induced by Con A. Moreover, DATS pretreatment alleviated the oxidative stress induced by Con A, which was evidenced by increased superoxide dismutase (SOD) and catalase (CAT) activities and decreased malondialdehyde (MDA) content in DATS and Con A co-treated mice compared with Con A alone group. Finally, DATS pretreatment reduced eosinophilic body formation, TUNEL positive staining and increased Bcl-2/Bax ratio in liver of Con A-injected mice, indicating attenuated apoptosis. SignificanceCollectively, the results suggest that DATS displays potent protective effects against Con A-induced acute liver injury in mice possibly through inhibition of inflammation, oxidative stress and apoptosis.

Summary of Natural Products Ameliorate Concanavalin A-Induced Liver Injury: Structures, Sources, Pharmacological Effects, and Mechanisms of Action.

Liver diseases represent a threat to human health and are a significant cause of mortality and morbidity worldwide. Autoimmune hepatitis (AIH) is a progressive and chronic hepatic inflammatory disease, which may lead to severe complications. Concanavalin A (Con A)-induced hepatic injury is regarded as an appropriate experimental model for investigating the pathology and mechanisms involved in liver injury mediated by immune cells as well as T cell-related liver disease. Despite the advances in modern medicine, the only available strategies to treat AIH, include the use of steroids either solely or with immunosuppressant drugs. Unfortunately, this currently available treatment is associated with significant side-effects. Therefore, there is an urgent need for safe and effective drugs to replace and/or supplement those in current use. Natural products have been utilized for treating liver disorders and have become a promising therapy for various liver disorders. In this review, the natural compounds and herbal formulations as well as extracts and/or fractions with protection against liver injury caused by Con A and the underlying possible mechanism(s) of action are reviewed. A total of 53 compounds from different structural classes are discussed and over 97 references are cited. The goal of this review is to attract the interest of pharmacologists, natural product researchers, and synthetic chemists for discovering novel drug candidates for treating immune-mediated liver injury.

Interleukin-39 exacerbates concanavalin A-induced liver injury

Background Interleukin (IL)-39 is a novel member of IL-12 family and has been reported to play a pro-inflammatory role in lupus-like mice, but its function in concanavalin A (ConA)-induced liver injury is currently unclear. Materials and methods In this study, we investigated the effects of IL-39 expression in a mouse model of ConA induced-hepatitis. We first showed that delivery of plasmid DNA encoding mouse IL-39 using the hydrodynamic tail vein injection method increased IL-39 mRNA and protein levels in the liver. We then administrated mice with IL-39 plasmid before ConA injection and measured serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, inflammatory infiltration, and hepatocyte necrosis in the liver. Additionally, we further explored the potential mechanism of IL-39 in ConA-induced liver injury by measuring several inflammatory mediators. Results We found that ectopic IL-39 expression promoted the ConA-induced increase in serum ALT and AST levels, inflammatory infiltration, and hepatocyte necrosis in the liver. We also observed that IL-39 plasmid administration significantly increased serum and liver interferon-γ, tumor necrosis factor-α, and IL-17A levels, but did not affect serum and liver IL-10 levels in ConA-induced hepatitis. Conclusion Our results suggest that IL-39 can exacerbate ConA-induced hepatitis and may be a therapeutic target in inflammatory liver disease.

Metabolomics study on the therapeutic mechanism of Schisandra chinensis polysaccharides on concanavalin A-induced immunological liver injury in mice

Background: Schisandra chinensis is a traditional Chinese herbal medicine which protects hepatic function. Its primary component is polysaccharides which is used in the treatment of hepatic injury, but the mechanism of action of S. chinensis polysaccharides (SCP) in immunological liver injury induced by concavalin A (Con A) is still not clear. Aim: In this study, we aimed to evaluate the hepatoprotective mechanism of SCP in immunological liver injury. Subjects and Methods: In this study, we performed rapid-resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry-based serum metabolomics approach to investigate the hepatoprotective effects of SCP against Con A-induced immunological liver injury in mice. Results: According to our results, SCP significantly increased the activity of superoxide dismutase in the liver; decreased the level of serum aspartate aminotransaminase (AST), serum alanine aminotransaminase (ALT), tumor necrosis factor-α, interferon-γ, interleukin (IL)-1 β, and IL-6 in the serum, and decreased the level of malondialdehyde and nitric oxide in the liver of mice with immunological liver injury induced by Con A. In this study, we identified 17 biomarkers through metabolomic analysis, and after the administration of SCP, 16 of them were found to return to the normal levels. Our analysis suggested that some metabolic pathways are involved in the mechanisms of action of SCP for the treatment of the immunological liver injury, including energy metabolism, amino acid metabolism, taurine metabolism, amino saccharide and nucleotide metabolism, arachidonic acid metabolism, and lipid metabolism. Conclusion: SCP could alleviate the oxidative stress and inflammatory reaction in the immunological liver injury and recover the metabolic dysfunction caused by Con A.

Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model.

Background: Concanavalin A (ConA)-induced liver damage of mice is a well-established murine model mimicking the human autoimmune hepatitis (AIH). However, the pathogenic genes of the liver injury remain to be revealed.Methods: Using time-series liver transcriptome, top dynamic genes were inferred from a set of segmented regression models, and cross-checked by weighted correlation network analysis (WGCNA). AIH murine models created by ConA were used to verify the in vivo effect of these genes.Results: We identified 115 top dynamic genes, of which most were overlapped with the hub genes determined by WGCNA. The expression of several top dynamic genes including Cd63, Saa3, Slc10a1, Nrxn1, Ugt2a3, were verified in vivo. Further, Cluster determinant 63 (Cd63) knockdown in mice treated with ConA showed significantly less liver pathology and inflammation as well as higher survival rates than the corresponding controls.Conclusion: We have identified the top dynamic genes related to the process of acute liver injury, and highlighted a targeted strategy for Cd63 might have utility for the protection of hepatocellular damage.